Pyrrolo[3,4-D][2]Benzazepines

ABSTRACT

The present invention relates to compounds of the formula ##STR1## wherein R 1  is selected from the group consisting of hydrogen, lower alkyl, C 3  to C 7  alkenyl or alkynyl, hydroxymethyl, the group ##STR2## wherein R 11  is hydrogen, hydroxy, alkoxy, amino and mono- or di-lower alkylamino; and R 3  is selected from the group consisting of hydrogen, lower alkyl, C 3  to C 7  alkenyl or alkynyl, hydroxymethyl, the group ##STR3## wherein R 11  is hydrogen, hydroxy, trihalomethyl, alkoxy, amino and mono- or di-lower alkylamino; R 2  is selected from the group consisting of hydrogen, lower alkyl, C 3  to C 7  alkenyl or alkynyl, the group ##STR4## C 2  to C 7  carboxylic acids and the esters and amides thereof, hydroxy C 2  to C 7  alkyl and amino or mono- or di-lower alkyl amino C 2  to C 7  alkyl; R 4  is selected from the group consisting of hydrogen, acyloxy, straight chain lower alkoxy and hydroxy; R 5  is halogen or hydrogen; R 6  is halogen with the proviso that if one of R 1  or R 3  is hydroxymethyl or the group ##STR5## wherein R 11  is as above then the remaining substituent is selected from the group consisting of hydrogen, lower alkyl and C 3  to C 7  alkenyl or alkynyl, and R 2  is hydrogen and the further proviso that (A) when R 4  is acyloxy then R 1  and R 3  are hydrogen, lower alkyl, C 3  to C 7  alkenyl or C 3  to C 7  alkynyl, and R 2   is the group ##STR6## (B) when R 4  is hydroxy then R 1  and R 3  are hydrogen, lower alkyl, C 3  to C 7  alkenyl or C 3  to C 7  alkynyl, and R 2  is hydrogen or (C) when R 4  is alkoxy then R 1  and R 3  are hydrogen, lower alkyl, C 3  to C 7  alkenyl or C 3  to C 7  alkynyl, and the pharmaceutically acceptable salts thereof. 
     Also disclosed are certain 5,6 dihydro derivatives, N-oxides and quarternary iminium salts of the pyrrolobenzazepines.

RELATED APPLICATIONS

This is a division of application Ser. No. 286,124, filed July 23, 1981,now U.S. Pat. No. 4,354,973, which is a continuation-in-part of Ser. No.175,555, filed Aug. 5, 1980, now abandoned.

The compounds exhibit pharmacological activity as sedatives andanxiolytics. Also disclosed are various intermediates and processes toproduce the novel end products.

DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the formula ##STR7##wherein R₁ is selected from the group consisting of hydrogen, loweralkyl, C₃ to C₇ alkenyl or alkynyl, hydroxymethyl, the group ##STR8##wherein R₁₁ is hydrogen, hydroxy, alkoxy, amino and mono- or di-loweralkylamino; and R₃ is selected from the group consisting of hydrogen,lower alkyl, C₃ to C₇ alkenyl or alkynyl, hydroxymethyl, the group##STR9## wherein R₁₁ is hydrogen, hydroxy, trihalomethyl, alkoxy, aminoand mono- or di-lower alkylamino; R₂ is selected from the groupconsisting of hydrogen, lower alkyl, C₃ to C₇ alkenyl or alkynyl, thegroup ##STR10## C₂ to C₇ carboxylic acids and the esters and amidesthereof, hydroxy C₂ to C₇ alkyl and amino or mono- or di-lower alkylamino C₂ to C₇ alkyl; R₄ is selected from the group consisting ofhydrogen, acyloxy, straight chain lower alkoxy and hydroxy; R₅ ishalogen or hydrogen; R₆ is halogen with the proviso that if one of R₁ orR₃ is hydroxymethyl or the group ##STR11## wherein R₁₁ is as above thenthe remaining substituent is selected from the group consisting ofhydrogen, lower alkyl and C₃ to C₇ alkenyl or alkynyl, and R₂ ishydrogen and the futher proviso that (A) when R₄ is acyloxy then R₁ andR₃ are hydrogen, lower alkyl, C₃ to C₇ alkenyl or C₃ to C₇ alkynyl, andR₂ is the group ##STR12## (B) when R₄ is hydroxy then R₁ and R₃ arehydrogen, lower alkyl, C₃ to C₇ alkenyl or C₃ to C₇ alkynyl, and R₂ ishydrogen or (C) when R₄ is alkoxy then R₁ and R₃ are hydrogen, loweralkyl, C₃ to C₇ alkenyl or C₃ to C₇ alkynyl, and the pharmaceuticallyacceptable salts thereof.

The compounds exhibit activity as sedative and anxiolytic agents.

By the term "halogen" or "halo" is meant bromo, chloro or fluoro exceptas limited herein.

By the term "lower alkyl" or "alkyl" is meant both straight and branchedchain C₁ to C₇ hydrocarbon groups, preferably C₁ to C₄ carbon-hydrogenradicals, such as, methyl, ethyl, propyl, isopropyl and the like.

By the term "C₃ to C₇ alkenyl or alkynyl" there is meant C₃ to C₇straight and branched chain hydrocarbon groups wherein at least onecarbon to carbon bond is unsaturated and depicted by a double or triplebond. The point of unsaturation cannot however be between the carbonwhich is attached to the pyrrole ring and the next adjacent carbon,i.e., the terminal attached carbon is not unsaturated.

By the term "acyl" is meant a radical derived from an organic acid bythe removal of the hydroxy goup, i.e., radicals of the formula ##STR13##wherein R is C₁ to C₆ alkyl or halo alkyl, phenyl or hydrogen, e.g.,acetyl, propionyl, butyryl, benzoyl, etc.

By the term "carboxylic acids and the esters and amides thereof" ismeant radicals of the formula -C₁ to C₆ lower alkyl- COR₂₁ where R₂₁ ishydroxy, lower alkoxy, amino or amino which is mono- or di-substitutedby lower alkyl.

Compounds of formula I wherein R₁ and R₃ are hydrogen, lower alkyl, C₃to C₇ alkenyl or C₃ to C₇ alkynyl, R₂ is as above but not amino or mono-or di-lower alkylamino C₂ to C₇ alkyl and R₄ is hydrogen can bequarternized at the imine functionality with a lower alkyl halide orsulfonate. The quarternary iminium salts thus obtained and compounds offormula I wherein R₁ and R₃ are hydrogen, lower alkyl, C₃ to C₇ alkenylor C₃ to C₇ alkynyl and R₄ is hydrogen can, if desired, be reduced withappropriate reducing agents, such as, lithium aluminum hydride, sodiumborohydride or sodium cyanoborohydride to afford the corresponding5-alkyl-5,6-dihydro or 5,6-dihydro derivative compounds.

The 5,6-dihydro derivatives and the quarternary iminium salts are alsoactive anxiolytic agents.

Compounds of formula I wherein R₁ and R₃ are hydrogen, lower alkyl, C₃to C₇ alkenyl and C₃ to C₇ alkynyl, R₂ is as above but not amino ormono- or di-lower alkylamino C₂ to C₇ alkyl, R₄ is hydrogen and R₅ andR₆ are as above may also undergo reaction to form imine oxides and theN-oxides thereof which are also active as anxiolytic agents.

The compounds of formula I may be prepared following the schemes below:##STR14## wherein R₅ and R₆ are as above.

II→III

The compound of formula II, a well-known starting material, is reactedwith zinc dust and cupric sulfate is concentrated ammonium hydroxide.Reaction temperatures range from about room temperature to 100° C. with100° C. preferred.

III→IV

The compound of formula III is reacted with a metal hydride, such as,lithium aluminum hydride or borane in an etherial solvent such asdiethyl ether or tetrahydrofuran. Reaction temperatures range from about-78° C. to room temperature with about 0° C. preferred.

IV→V

The compound of formula IV is reacted with pyridinium chlorochromate,manganese dioxide or other suitable oxidizing agents using methylenechloride as solvent. Reaction temperatures range from about 0° C. to thereflux temperature of the solvent with about room temperature aspreferred.

V→VI

The compound of formula V is reacted with diethyl cyanomethylphosphonatein the presence of a strong base such as sodium hydride, sodium amideetc. and using an etherial solvent, such as, tetrahydrofuran. Reactiontemperatures range from about 0° C. to room temperature with about roomtemperature preferred.

VI→VII

The compound of formula VI is reacted with chromium trioxide or anoxidizing agent derived from chromium trioxide in a mixture of aceticacid and methylene chloride. Reaction temperatures range from about 0°C. to about 90° C. with room temperature preferred.

VIII→IX

The compound of formula VIII i.e., the amino ketone is a well-knownstarting material. The compound is reacted wih acrylonitrile in thepresence of acetonitrile, a lower alkyl nitrite and cupric chloride. Thereaction temperature may range from about 0° C. to about 40° C. withabout room temperature as preferred.

IX→VII

The compound of formula IX above is reacted with an alkali metal, e.g.,lithium, sodium or potassium carbonate and bi-carbonate mixturepreferably a mixture of one part potassium carbonate to three partspotassium bicarbonate. Suitable solvents include dimethyl sulfoxide,dimethylformamide or C₁ to C₄ alcohols, e.g., methanol. Reactiontemperature ranges from about 20° C. to 50° C. with room temperaturepreferred. The above reaction represents a dehydrohalogenation which iswell-known in the art.

VII→X

The compound of formula VIII may be diazotized using sodium nitrite insulfuric acid and the diazonium salt may be isolated by precipitatingthe respective tetrafluoroborate salts. These salts are slurried inwater and treated with aqueous potassium iodide at room temperature togive the iodobenzophenone X.

X→VII

The compound of formula X is reacted with acrylonitrile in the presenceof a palladium II salt, such as, acetate, chloride, etc. usingacetonitrile or an aromatic hydrocarbon, such as, toluene as solvent.Reaction temperatures range from about 60° C. to the reflux temperatureof the solvent with reflux temperature preferred. ##STR15## wherein R₁ "is hydrogen, lower alkyl, C₃ to C₇ alkenyl or alkynyl, R₁ '" is hydrogenor lower alkyl and R₅ and R₆ are as above.

VII→XI

The compound of formula VII is reacted with an α-tosyl alkylisocyanide,an α-tosyl C₄ to C₈ alkenyl isocyamide and an α-tosyl C₄ to C₈ alkynylisocyamide in the presence of sodium hydride using a mixture ofdimethylsulfoxide and an ether, such as, diethylether, dioxane ortetrahydrofuran as solvent. The reaction temperatures range from about0° C. to about 40° C. with room temperature preferred. The α-tosylisocyanides mentioned above may be prepared following the teaching ofvan Leusen et al., Tetrahedron Letters, 3487 (1975).

XI→Ia

The compound of formula XI is reacted with hydrogen at pressure rangingfrom about atmospheric pressure to five atmospheres in the presence of atransition metal catalyst, such as, Raney nickel using glacial aceticacid as solvent. The resulting amine thus formed cyclizes spontaneouslyto the azepine ring. Reaction temperature is about room temperature.

The first formed ring open amine is not isolated but is allowed tocyclize in situ to product Ia.

XI→XII

The compound of formula XI is reacted with a metal hydride reducingagent, such as, lithium aluminum hydride in an etherial solvent such astetrahydrofuran. Reaction temperature ranges from about -20° C. to roomtemperature with 0° C. preferred.

XII→Ib

The compound of formula XII is reacted with manganese dioxide in anether solvent, such as, tetrahydrofuran or a solvent, such as, toluene.The resulting amine thus formed cyclizes spontaneously to the azepinering. Reaction temperature ranges from about room temperature to theboiling point of the solvent with 40° C. preferred. ##STR16## wherein R₁' and R₃ ' are lower alkyl, C₃ to C₇ alkenyl or alkynyl and R₅ and R₆are as above.

Ia→Ib'+Ic'

The compound of formula Ia is reacted with one equivalent of a strongbase such as lithium diisopropylamide at between -78° C. to about 0° C.with about -20° C. preferred. The resulting anion is treated with thedesired alkylating agent, such as, a lower alkyl, C₃ to C₇ alkenyl or C₃to C₇ alkynyl halide or sulfonate. A mixture of Ib' and Ic' isomersresults which can be separated by column chromatography.

Ib'→Id and Ic'→Id

The reaction conditions are the same as the conversion of Ia into Ib'and Ic'. The same or different alkylating agents may be utilized so thatsymmetrical or nonsymmetrical compounds may be produced. ##STR17##wherein R₅ and R₆ are as above, R₁ " and R₃ " are hydrogen, lower alkyl,C₃ to C₇ alkenyl or C₃ to C₇ alkynyl, n is 1 to 6, R₉₁ and R₉₂ arehydrogen or lower alkyl, R₈₂ is lower alkyl, C₃ to C₇ alkenyl or C₃ toC₇ alkynyl

If→Iu

A compound of the formula If is reacted with a halo ester such as ethylbromoacetate, ethyl 3-bromopropionate in the presence of an alkali metalalkoxide in a polar solvent such as dimethyl sulfoxide ordimethylformamide. Reaction temperature ranges from about -20° C. toroom temperature with 0° C. preferred. If desired, the end product maybe treated with an alkali metal carbonate or hydroxide in an aqueousethereal solvent, such as, tetrahydrofuran. Subsequent addition of astrong mineral acid yields the corresponding carboxylic acid.

Iu→Iv

A compound of the formula Iu is reacted with ammonia or a mono- ordi-substituted lower alkyl amine and a catalytic amount of itshydrochloride salt with a C₁ to C₄ alcohol solvent. The reaction isusually conducted at 100° C. using a pressure apparatus to contain thevolatile reactants.

Iu→Iw

A compound of the formula Iu is reacted with a metal hydride such aslithium aluminum hydride in an etherial solvent such as tetrahydrofuranor dioxane. Reaction temperature ranges from -78° C. to room temperaturewith 0° C. as preferred.

If→Ix

A compound of the formula If is reacted with a compound of the formula##STR18## wherein R₉₁ and R₉₂ are hydrogen or lower alkyl, X is halogenand n is as above in the presence of an alkali metal alkoxide in a polarsolvent such as dimethyl sulfoxide or dimethylformamide. The reactiontemperature ranges from -20° C. to room temperature with roomtemperature preferred.

If→Iy

A compound of the formula If is reacted with an alkali metal alkoxidefollowed by a haloformate, such as, methyl chloroformate, benzylchloroformate, etc. in a polar solvent, such as, dimethyl sulfoxide ordimethylformamide. The reaction temperature ranges from -20° C. to roomtemperature with 0° C. preferred.

If→Iz

A compound of the formula If is reacted with an alkali metal alkoxide,such as, potassium or sodium methoxide followed by an alkylating agent,or i.e., a lower alkyl, C₃ to C₇ alkenyl or C₃ to C₇ alkynyl, halide orsulfonate in a polar aprotic solvent, e.g., dimethylformamide ordimethylsulfoxide. The reaction temperature ranges from 0° C. to roomtemperature with 0° C. preferred.

Iv→Ix

A compound of the formula Iv is reacted with a metal hydride reducingagent, such as, lithium aluminum hydride in an ether solvent, such as,tetrahydrofuran. The reaction temperature ranges from -20° C. to roomtemperature with 0° C. as preferred.

If→Iw

The compound of formula If in the presence of an alkali metal alkoxideand dimethylformamide or dimethylsulfoxide is reacted with a compound ofthe formula

    X-(CH.sub.2).sub.n+1 -OR.sub.80

wherein R₈₀ is a hydroxy protecting group, X is halogen and n is asabove.

Suitable hydroxy protecting groups include the tetrahydropyranyl ethergroup. Subsequent treatment with aqueous acid yields the end product.

If→Iv

The compound of formula If reacted with a compound of the formula##STR19## wherein R₉₁ and R₉₂ are as above, X is halogen and n is asabove in the presence of a alkal metal alkoxide and dimethylformamide ordimethyl sulfoxide. ##STR20## wherein R₁ ", R₃ ", R₅ and R₆ are asabove.

Ib→Ij and Ic→Il

Compounds of the formulas Ib and Ic are reacted with a mixture ofdimethylformamide and phosphoryl chloride (phosgene, thionyl chloride oroxalyl chloride may also be used) with or without a solvent, such as,methylene chloride. The reaction is usually carried out at about 0° C.

Ij→Ik and Il→Im

Compounds of the formulas Ij and Il are reacted with sodium borohydridein a C₁ to C₄ alcohol with ethanol being preferred, at between -20° C.to room temperature with 0° C. preferred.

Ib→Ik and Ic→Im

compounds of the formulas Ib and Ic are reacted with paraformaldehyde inthe presence of an alkali metal carbonate in a C₁ to C₄ alcohol withmethanol being preferred. Reaction temperatures range from about 0° C.to the boiling point of the solvent with room temperature preferred.##STR21## wherein R₃₅ is hydrogen or lower alkyl, X is halo and R₁ " andR₃ " are as above.

Ib→In

The compound of formula Ib is reacted with a trihaloacetyl halide in thepresence of an inert solvent, such as, methylene chloride or diethylether. Reaction temperatures range from room temperature to the refluxtemperature of the solvent with the reflux temperature preferred.

In→Io

The compound of formula In is reacted with the alkali metal alkoxideusing the corresponding alcohol as solvent. The reaction temperture isusually between 0° C. and room temperature.

In→Ip

The compound of formula In is reacted with ammonia or the correspondingamine in a C₁ to C₄ alcohol solvent. The temperatures vary from roomtemperature to 100° C. with 100° preferred. In those cases where thereactants have boiling points lower than the reaction temperature apressure apparatus is used to contain the reactants.

Ij→Iq and Il→Ir

Compounds of the formulas Ij or Il are reacted with potassiumpermanganate in a mixture of water and a water miscible inert solvent,such as, acetone, tetrahydrofuran, etc. Reaction temperatures vary fromabout 0° C. to 60° C. with room temperature preferred.

Iq→Io and Ir→It

Compounds of the formulas Iq and Ir are reacted with a diazoalkane suchas diazomethane or diazoethane in an inert solvent such as methylenechloride or a low boiling ether, such as, diethyl ether,tetrahydrofuran, etc. The reactions are usually performed at between 0°C. and room temperature.

Compounds of the formulas Iq and Ir are alternatively dissolved in thecorresponding alcohol containing a catalytic amount of strong mineralacid, such as, sulfuric acid or an organic acid such asp-toluenesulfonic acid. The reaction temperatures vary from roomtemperature to reflux temperature of the alcohol with room temperaturepreferred.

Io→Ip and It→Is

Compounds of the formulas Io and It are reacted with ammonia or a mono-or dilower alkyl amine and a catalytic amount of their hydrochloridesalts in, optionally, a C₁ to C₄ alcohol solvent. The reactiontemperatures vary from room temperature to 100° C. with 100° C. aspreferred. In those cases where the reactants or solvents have boilingpoints lower than 100° C. a pressure apparatus is used to contain thereactants. ##STR22## R₄₅ is lower alkyl or trifluoromethyl, R₅₅ isstraight chain lower alkyl, R₂ is as above and R₁ ", R₃ ", R₅ and R₆ areas above.

Iy→Iaa

A compound of the formula Iy is reacted with a peracid such asm-chloroperoxybenzoic acid, pertifluoroacetic acid, etc. in an inertsolvent such as methylene chloride. The reaction temperature ranges from0° C. to the reflux temperature of the solvent with room temperaturepreferred.

Iaa→Ibb

A compound of the formula Iaa is reacted with an acid anhydride selectedfrom suitable carboxylic acids such as acetic or trifluoroaceticanhydride. The reaction is preferably done at about the refluxtemperature of the anhydride chosen however not to exceed about 130° C.

Ibb→Icc

Ibb is reacted with an alkali metal hydroxide, e.g., sodium or potassiumhydroxide in an aqueous ethereal solution, e.g., a H₂ O/dioxane ortetrahydrofuran mixture. The reaction may be run at from about 0° C. toroom temperature with about room temperature as preferred.

Ibb→Idd

The compound of the formula Ibb is reacted with an alkali metalhydroxide or alkoxide, e.g., sodium or potassium hydroxide or methoxidein a mixture of a C₁ to C₇ straight chain alcohol and an ether, e.g.,tetrahydrofuran or dioxane. The reaction is carried out from about 0° C.to room temperature with about 0° C. as preferred.

Idd→Iee

The compound of the formula Idd is thereafter reacted following thereaction parameters set forth in Scheme IV, i.e., steps If→Iu; If→Iv;If→Iw; Iu→Iv; Iu→Iw; If→Ix; If→Iy; If→Iz and Iv→Ix.

If→Iff

A compound of the formula If is reacted with a peracid such asm-chloroperoxybenzoic acid, pertifluoroacetic acid, etc. in an inertsolvent such as methylene chloride. The reaction temperature ranges fromabout -20° C. to room temperature with 0° C. preferred. Furthermore itshould be noted, although not shown in the above Scheme, that thecompounds of formulas Iu, Iv, Iw or Iz can be reacted as above, i.e.undergo a 5-oxidation.

Iaa→Iff

The compound of the formula Iaa is reacted with an alkali metalhydroxide or carbonate, e.g., sodium hydroxide or potassium carbonate ina mixture of a C₁ to C₇ straight chain alcohol and an ether, e.g.,tetrahydrofuran. The reaction is carried out from about 0° C. to thereflux temperature of the solvent with room temperature as preferred.##STR23## wherein R₉₅ is lower alkyl, R₂ " is equal to R₂ with theexception that it cannot be amino, mono- or di- alkylamino C₂ to C₇alkyl, R₁ ", R₂, R₃ ", R₅ and R₆ are as above and X is a halide orsulfonate radical

Igg→Ihh

A compound of the formula Igg is reacted with a reducing agent, such as,sodium cyanoborohydride in a C₁ to C₃ alcohol solvent containing amineral acid or zinc in acetic acid. The reaction temperature rangesfrom -20° C. to room temperature with 0° C. preferred.

Iii→Ijj

A compound of the formula Iii is reacted with a lower alkyl halide orsulfonate in a polar aprotic solvent, such as, dimethylformamide ordimethyl sulfoxide. The reaction temperature ranges from 0° C. to 40° C.with room temperature preferred. If R₂ " in Iii is hydrogen andalkylation is effected in presence of base, then R₂ " in Ijj is equal toR₉₅ ".

Ijj→Ikk

A compound of the formula Ijj is reacted with a reducing agent, such as,sodium borohydride or sodium cyanoborohydride in a C₁ to C₃ alcoholsolvent. The reaction temperature ranges from -20° C. to roomtemperature with room temperature preferred. In the case where R₂ " isC₂ to C₇ carboxylic acid amide (Iv) a stronger reducing agent, such as,lithium aluminum hydride in an ether solvent, such as, tetrahydrofuranmay be used to provide a full value for R₂. Reaction temperature rangesfrom -78° C. to room temperature with 0° C. preferred.

Compounds of formula I which are preferred are as those wherein R₃ ishydrogen and R₅ and R₆ are halogen, R₁ is hydrogen or lower alkyl, R₂ isas above and R₄ is hydrogen.

Especially preferred compounds are those of the formulas:

8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine;

8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine;

8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine;and

8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine.

8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-ethanol.

8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylicacid methyl ester.

The expression "pharmaceutically acceptable salts" is used to includesalts with both inorganic and organic pharmaceutically acceptable strongacids, such as, sulfuric acid, hydrochloric acid, nitric acid,methanesulfonic acid and p-toluenesulfonic acid. Such salts can beformed quite readily by those skilled in the art with the prior art andthe nature of the compound to be placed in salt form in view.

The pyrrolo[3,4-d][2]benzazepines above are useful as pharmaceuticalsand are characterized by activity as sedatives and anxiolytic agents.These compounds can be used in the form of conventional pharmaceuticalpreparations; for example, the aforesaid compounds can be mixed withconventional organic or inorganic, inert pharmaceutical carrierssuitable for parenteral or enteral administration such as for example,water gelatin, lactose, starch, magnesium stearate, talc, vegetable oil,gums, polyalkylene glycols, Vaseline or the like. They can beadministered in conventional pharmaceutical forms, e.g., solid forms,for example, tablets, dragees, capsules, suppositories or the like, orin liquid forms, for example, solutions, suspensions or emulsions.Moreover, the pharmaceutical compositions containing compounds of thisinvention can be subjected to conventional pharmaceutical expedientssuch as sterilization, and can contain conventional pharmaceuticalexcipients such as preservatives, stabilizing agents, wetting agents,emulsifying agents, salts for the adjustment of osmotic pressure, orbuffers. The compositions can also contain other therapeutically activematerials.

A suitable pharmaceutical dosage unit can contain from about 1 to about500 mg of the benzazepine end products with a dosage range of from about1 mg to about 100 mg being the preferred oral administration and adosage range of from about 1 mg to about 50 mg being preferred forparenteral administration. However, for any particular subject, thespecific dosage regimen should be adjusted according to individual needand the professional judgement of the person administering orsupervising the administration of the aforesaid compounds. It is to beunderstood that the dosages set forth herein are exemplary only and thatthey do not, to any extent, limit the scope or practice of thisinvention.

The term "dosage unit" as employed throughout this specification refersto pharamceutically discrete units suitable as unitary dosages formammalian subject such containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical diluent, carrier orvehicle.

The following data is indicative of the pharmacological activities ofthe pyrrolobenzazepines utilizing pharmacological tests well-known inthe art.

    __________________________________________________________________________                    Test                                                          Compound        Footshock Inclined Screen                                                                       Unanesthetized Cat                          __________________________________________________________________________    8-chloro-6-phenyl-2H,4H--                                                                     25 mg/kg  400 mg/kg                                                                             2.5  mg/kg                                  pyrrolo[3,4-d] [2] benzazepine                                                Toxicity (LD.sub.50) = greater than                                                           1000                                                                             mg/kg (PO)                                                 8-chloro-6-(2-chlorophenyl)-                                                                  1  mg/kg  400 mg/kg                                                                             0.25 mg/kg                                  2H,4H--pyrrolo[3,4-d] [2] benza-                                              zepine                                                                        Toxicity (LD.sub.50) = greater than                                                           1000                                                                             mg/kg (PO)                                                 8-chloro-6-(2-fluorophenyl)-                                                                  2  mg/kg  400 mg/kg                                                                             2.5  mg/kg                                  1-methyl-2H,4H--pyrrolo[3,4-d]-                                               [2] benzazepine methane-                                                      sulfonate                                                                     Toxicity (LD.sub.50) greater than                                                             1000                                                                             mg/kg (PO)                                                 __________________________________________________________________________

Brief description of the above tests are as follows:

Footshock

A pair of mice is confined under a one liter beaker placed on a gridwhich presents shock to the feet. At least 5 fighting episodes areelicited in a two-minute period. Pairs of mice are marked and pretreated1 hour prior to a second shocking. Logarithmic dose intervals areutilized up to a maximum of 100 mg/kg. At the 100% blocking dose, 3 outof 3 pairs must be blocked from fighting.

Inclined Screen

Groups of 6 male mice are given the test drug (maximum dose of 500mg/kg) and then are left on the inclined screen at least 4 hours forobservation of paralyzing effects severe enough to cause them to slideoff the screen. If activity is observed, additional doses are takenuntil at least two are reached at which some, but not all of the animalsslide off the screen. Doses at which mice fall off the screen due totoxicity or excitation are not included in the calculation of PD₅₀.

Unanesthetized Cat

Cats are treated orally and observed for minimum symptoms--usuallyataxia. One cat is used at a dose of 50 mg/kg. If activity is present,up to three cats/dose are used. Results are given as minimum effectivedose.

The following examples are illustrative, but not limitative of thisinvention. All temperatures given are in degrees centigrade, unlessindicated otherwise.

EXAMPLE 1 2-Benzyl-4-chlorobenzoic Acid

To a solution of 5.0 g of cupric sulfate in 3 liters of concentratedammonium hydroxide was added 300 g (4.6 mole) of activated zinc dust and100 g (0.42 mole) of 2-benzoyl-4-chlorobenzoic acid. The mixture wasrefluxed for 3 days, during which the volume was maintained by theaddition of concentrated ammonium hydroxide. The mixture was cooled, andthe excess zinc was removed by filtration. The filtrate was acidified bythe addition of concentrated hydrochloric acid to a pH of 3. Theresulting percipitate was collected by filtration, and dried to constantweight to give a white solid with mp 142°-144°.

EXAMPLE 2 2-Benzyl-4-chlorobenzyl alcohol

To a solution of 28.4 g (0.75 mole) of lithium aluminum hydride in 800ml of ether, which was cooled to 0°, was added dropwise 85.1 g (0.345mmole) of 2-benzyl-4-chlorobenzoic acid in 250 ml of ether. The mixturewas allowed to warm to room temperature, and was stirred for 2 hr. Theexcess lithium alluminum hydride was discharged by the addition of 28.5ml of water, 28.5 ml of 10% aqueous sodium hydroxide, and 85.5 ml ofwater. The precipitate was removed by filtration and the filtrate wasdried with sodium sulfate. Removal of the ether at reduced pressure gavea colorless oil which crystallized upon standing, mp 46.5°-49°.

EXAMPLE 3 2-Benzyl-4-chlorobenzaldehyde

To a suspension of 238 g (1.1 mole) of pyridinium chlorochromate and 800ml of methylene chloride was added 79.3 g (0.34-mole) of2-benzyl-7-chlorobenzyl alcohol. The mixture was stirred at roomtemperature for 2 hr. The chromium salts were percipitated by theaddition of 2.4 liters of 1:1 ether:petroleum ether, and the precipitatewas removed by filtration through Celite. The solvent was removed atreduced pressure to give a yellow oil, which was used without furtherpurification.

EXAMPLE 4 3-[2-Benzyl-4-chlorophenyl]-2-propenenitrile

To a suspension of 10.5 g (0.437 mole) of mineral oil free sodiumhydride in 1.2 liters of tetrahydrofuran was added dropwise 58.4 g(0.328 mole) of diethylcyanomethyl phosphonate. After the hydrogenevolution had ceased ca 60 min, 69.4 g (0.3 mole) of2-benzyl-4-chlorobenzaldehyde, in 75 ml of tetrahydrofuran was addeddropwise. The mixture was stirred overnight at room temperature. Thetetrahydrofuran solution was decanted, and concentrated at roomtemperature. The residue was partitioned between 2 liters of water and1.5 liters of ether. The ether solution was separated, washed withwater, and dried with sodium sulfate. The ether was removed at reducedpressure to give a yellow oil which was used without furtherpurification.

EXAMPLE 5 3-(2-Benoyl-4-chlorophenyl)-2-propenenitrile

A mixture of 28.8 g (0.14 mole) of3-[2-benzyl-4-chlorophenyl]-2-propenentrile, 50 g (0.5 mole) of chromiumtrioxide, 100 ml of methylene chloride, and 300 ml of acetic acid wasstirred at room temperature overnight. The excess chromium trioxide wasdischarged by the slow addition of 30 ml of ethanol. The mixture wasdiluted with 800 ml of water, and extracted with 500 ml of ether. Theether solution was washed with water, saturated aqueous sodiumbicarbonate, and saturated aqueous sodium chloride. The ether solutionwas dried with anhydros sodium sulfate, and concentrated at reducedpressure to give a yellow oil which was used without furtherpurification.

A sample of the product was purified by preparative layer chromatography(SiO₂ ; 2 mm; 1:1 methylene chloride:pentane) to give a white solid, mp87°-89°.

EXAMPLE 6 4-[2-Benzoyl-4-chlorophenyl]-1H-pyrrole-3-carbonitrile

A mixture of 10.7 g (40 mmole) of3-(2-benzoyl-4-chlorophenyl)-2-propenenitrile, 5.3 g (38 mmole) oftosylmethyl isocyanide, 75 ml of dimethyl sulfoxide and 150 ml of etherwas added dropwise to a suspension of 3.7 g (77 mmole) of 50% sodiumhydride in mineral oil and 170 ml of ether. When the addition wascomplete stirring was continued for 2 hr. The mixture was diluted withwater and the ether layer was separated. The aqueous solution wasextracted with ether. The combined ether extracts were washed withwater, dried over anhydrous sodium sulfate; and concentrated at reducedpressure to give a dark green oil. Purification by column chromatography(800 g silica gel; eluent 5% ether in methylene chloride) gave endproduct as off-white prisims, mp 175°-177°.

EXAMPLE 7 8-Chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine

A mixture of 4.0 g (13 mmole) of4-[2-benzoyl-4-chlorophenyl]-1H-pyrrole-3-carbonitrile, 4 g of Raneynickel, and 300 ml of acetic acid were hydrogenated on a Parr apparatusfor 4 hr. The Raney nickel was removed by filtration, and the filtratewas diluted with 400 ml of ice water. The acetic acid was neutralizedwith sodium bicarbonate, and the resulting solution extracted withmethylene chloride. The methylene chloride solution was washed withwater, and was dried with sodium sulfate. Concentration of the methylenechloride solution gave a yellow solid. Recrystallization from methylenechloride/ether gave a white solid, mp 203°-206°.

EXAMPLE 8 3-[2(2-Fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile

The preparation of3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile was conducted inthe same manner as the preparation of3-(2-benzoyl-4-chlorophenyl)-2-propenenitrile to give off-white prisms,mp 137°-139°.

EXAMPLE 94-[2-(2-Fluorobenzoyl)-4-chlorophenyl]-1H-pyrrole-3-carbonitrile

The preparation of4-[2-(2-fluorobenzoyl)-4-chlorophenyl]-1H-pyrrole-3-carbonitrile wasconducted in the same manner as the preparation of4-[2-benzoyl-4-chlorophenyl]-1H-pyrrolo-3-carbonitrile to give off-whiteprisims, mp 177°-179°.

EXAMPLE 108-Chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine

A mixture of 3.0 g (9 mmole) of4-[2-(2-fluorobenzoyl)-4-chlorophenyl]-1H-pyrrole-3-carbonitrile, ca 3 gof Raney nickel and 150 ml of glacial acetic acid was hydrogenated on aParr apparatus at 50 psi for 6 hr. The Raney nickel was removed byfiltration, and the acetic acid was removed at reduced pressure to givea yellow oil. The yellow oil was poured over ice, basified with ammoniumhydroxide and extracted with methylene chloride. The methylene chloridesolution was dried over anhydrous sodium sulfate and concentrated atreduced pressure to give tan crystals. Recrystallization from a mixtureof ether and methylene chloride gave cream prisms, mp 197°-199°.

EXAMPLE 118-Chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine methanesulfonate

The methanesulfonate salt of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine wasprepared by the addition of equimolar amounts of the benzazepine andmethanesulfonic acid to methanol and by percipitating the resulting saltby the addition of ether. Recrystallization of the salt from a mixtureof methanol and ether gave orange prisms, mp 220°-221°.

EXAMPLE 12 3-[2-(2-Chlorobenzoyl)-4-chlorophenyl]-2-propenenitrile

The preparation of3-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-propenenitrile was conducted inthe same manner as the preparation of3-(2-benzoyl-4-chlorophenyl)-2-propenenitrile to give off-white prisms,mp 137°-139°.

EXAMPLE 134-[2-(2-Chlorobenzoyl)-4-chlorophenyl]-1H-pyrrole-3-carbonitrile

The preparation of4-[2-(2-chlorobenzoyl)-4-chlorophenyl]-1H-pyrrole-3-carbonitrile wasconducted in the same manner as the preparation of4-[2-benzoyl-4-chlorophenyl]-1H-pyrrole-3-carbonitrile to give off-whiteprisms, mp 182°-184°.

EXAMPLE 148-Chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine

The preparation of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine wasconducted in the same manner as the preparation of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine to givecream prisms, mp 204°-206°.

EXAMPLE 158-Chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine methanesulfonate

The methanesulfonate salt of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine wasprepared by the addition of equimolar amounts of the benzazepine andmethanesulfonic acid to methanol and by precipitating the resulting saltby the addition of ether. Recrystallization of the salt from a mixtureof methanol and ether gave orange prisms, mp 239°-241°.

EXAMPLE 164-[2-(2-Fluorobenzoyl)-4-chlorophenyl]-5-methyl-1H-pyrrole-3-carbonitrile

A mixture of 34.5 g (121 mmole) of3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile, 25.3 g (121mmole) of 1-tosylethyl isocyanide, 200 ml of dimethyl sulfoxide and 400ml of ether was added dropwise to a suspension of 8.9 g (184 mmole) of50% sodium hydride in mineral oil and 450 ml of ether. When the additionwas complete stirring was continued for 2 hr. The mixture was dilutedwith water and the ether layer was separated. The aqueous solution wasextracted with ether. The combined ether extracts were washed withwater, dried over anhydrous sodium sulfate, and concentrated at reducedpressure to give a dark oil. Crystallization from ether gave off-whitecrystals. A small portion was recrystallized from a mixture of methylenechloride and ether to give colorless prisms, mp 201°-202°.

EXAMPLE 178-Chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine

The preparation of8-chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepinewas conducted in the same manner as the preparation of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine to givecolorless prisms, mp 226°-227°.

EXAMPLE 188-Chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepinemethanesulfonate

The methanesulfonate salt of8-chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepinewas prepared by the addition of equimolar amounts of the benzazepine andmethanesulfonic acid to methanol and isolated by precipitating the saltby the addition of ether. Recrystallization of the salt from a mixtureof methanol and ether gave orange prisms, mp 259°-261°.

EXAMPLE 198-Chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-1-carboxaldehydeand 8-Chloro-6-phenyl-4H-pyrrole[3,4-d][2]benzazepine-3-carboxaldehyde

Phosphorous oxychloride, 0.6 ml, was added to a solution of 0.6 g (2.06mmole) of 8-chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine in 8 mlof dimethylformamide cooled in ice-water. The mixture was stirred for 1hr with cooling and was then poured into 10% aqueous sodium carbonatesolution. The precipitated product was collected and dissolved inmethylene chloride. The solution was dried and evaporated. The residue(0.55 g) was chromatographed over silica gel using 20% (v/v) of ethylacetate in methylene chloride for elution. The less polar3-carboxaldehyde was crystallized from ether and recrystallized fromethyl acetate/hexane, mp 225°-226°.

EXAMPLE 208-Chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-3-methanol and8-chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-1-methanol

Phosphorous oxychloride, 5 ml, was added to a solution of 3 g (0.013mol) of 8-chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine in 40 ml ofdimethylformamide cooled in ice-water. After stirring and cooling for 1hr, the reaction mixture was poured into 10% aqueous sodium carbonatesolution. The precipitated product was collected and dissolved inmethylene chloride. The solution was dried and evaporated and theresidue was dissolved in 100 ml of ethanol. Following the addition of0.8 g of sodium borohydride the mixture was stirred at room temperaturefor 30 min. The solvent was partially evaporated under reduced pressureand the remainder was partitioned between methylene chloride and water.The organic layer was dried and evaporated and the residue waschromatographed over 250 g of silica gel using methylene chloride/ethylacetate 2:3.

The first eluted8-chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-1-methanol wascrystallized from ethyl acetate to yield off-white crystals with mp208°-210°.

The more polar8-chloro-6-phenyl-4H-pyrrolo[3,4-d][2]benzazepine-3-methanol wascrystallized from ethyl acetate and yielded off-white crystals with mp216°-218°.

EXAMPLE 21 8-Chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-aceticacid ethyl ester

To a solution of 1.4 g (12.4 mmole) of potassium t-butoxide in 30 ml ofdry dimethylformamide was added 2.4 g (8.2 mmole) of8-chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine. The mixture wascooled to 0°, and stirred for 10 min. To the mixture was added 1.3 mol(11.7 mmole) of ethyl bromoacetate. The mixture was stirred at 0° for 45min, diluted with water, and extracted with ether. The ether solutionwas washed with water, dried with sodium sulfate, and concentrated atreduced pressure to give a yellow oil. Purification by columnchromatography (70 g SiO₂, 9:1 methylene chloride/ether) gave as thefirst major component a yellow oil.

A second component consisted of recovered starting material mp202°-204°.

EXAMPLE 228-Chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetamide

A mixture of 2.3 g (6.5 mmole) of8-chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid ethylester and 20 ml of methanolic ammonia (ca 20% v/v) was heated in anautoclave on a steambath overnight. The solvent was removed at reducedpressure to give a light yellow solid. Recrystallization fromethanol-hexane gave a white solid, mp 236°-237°.

EXAMPLE 23 α,4-Dichloro-2-(benzoyl)-benzenepropanenitrile

A solution of 92.7 g (0.4 mole) of 2-amino-5-chlorobenzephenone in 250ml of acetonitrile was added to a mixture of 70 g (0.52 mole) of cupricchloride, 65 g (0.63 mole) of t-butylnitrile, 500 ml of acrylonitrile,and 500 ml of acetonitrile. When the addition was complete stirring atroom temperature was continued for 2 hr. The mixture was diluted with 80ml of 6 N hydrochloric acid and 1500 ml of water, extracted with etherand dried over anhydrous sodium sulfate. The ether solution wasconcentrated at reduced pressure to give a brown oil, which containedthe end product and 2,5-dichlorobenzophenone. Trituration of the oilwith a mixture of ether and petroleum ether gave the end product as atan solid. Recrystallization of a small portion of the end product froma mixture of ether and petroleum ether gave pale yellow needles, mp69°-71°.

EXAMPLE 24 α,4-Dichloro-2-(2-fluorobenzoyl)-benzenepropanenitrile

The preparation ofα-4-dichloro-2-(2-fluorobenzoyl)-benzenepropanenitrile was conducted inthe same manner as the preparation ofa-4-dichloro-2-(benzoyl)-benzenepropanenitrile to give pale yellowprisms, mp 94°-95°.

EXAMPLE 25 α4-Dichloro-2-(2-chlorobenzoyl)-benzenepropanenitrile

The preparation ofa-4-dichloro-2-(2-chlorobenzoyl)-benzenepropanenitrile was conducted inthe same manner as the preparation ofa-4-dichloro-2-(benzoyl)-benzenepropanenitrile to give off-white prisms,mp 102°-103°.

EXAMPLE 26 3-(2-Benzoyl-4-chlorophenyl)-2-propenenitrile

A mixture of 50.9 g (0.168 mole) ofa-4-dichloro-2-(benzoyl)-benzenepropanenitrile, 17g (0.14 mole) ofpotassium carbonate, 50.9 g (0.5 mole) of potassium bicarbonate and 510ml of dimethyl sulfoxide was stirred at room temperature for 48 hr. Themixture was diluted with 1.5 l of water, and the resulting percipitatewas collected by filtration. Recrystallization from a mixture ofmethylene chloride and ether gave off-white prisms, mp 89°-91°.

EXAMPLE 278-Chloro-6-(2-fluorophenyl)-1-methyl-3-[(trichloromethyl)carbonyl]-2H,4H-pyrrolo[3,4-d][2]benzazepine

A mixture of 3.4 g (11 mmole) of8-chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine,2.6 g (14 mmole) of trichloroacetyl chloride, and 100 ml of methylenechloride was stirred at room temperature for 12 hr. The resultingprecipitate was collected by filtration, resuspended in methylenechloride, and basified with ammonium hydroxide. The methylene chloridesolution was separated, dried over anhydrous sodium sulfate, andconcentrated at reduced pressure to give a (mp 222°-225°) colorlesssolid. A small portion was recrystallized from a mixture of methylenechloride and ether to give colorless prisms, mp 222°-223°.

EXAMPLE 288-Chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo-[3,4-d][2]benzazepine-3-carboxylicacid methyl ester

A mixture of 3.0 g (6.4 mmole) of8-chloro-6-(2-fluorophenyl)-1-methyl-3-[(trichloromethyl)carbonyl]-2H,4H-pyrrolo[3,4-d][2]benzazepine,0.5 ml (2 mmole) of a 4 M methanol solution of sodium methoxide and 100ml of methanol was heated to 40° for 30 min. The methanol solution wasconcentrated at reduced pressure, and the residue was partitionedbetween methylene chloride and water. The methylene chloride solutionwas dried with anhydrous sodium sulfate and concentrated at reducedpressure to give (mp 228°-231°) tan needles. Recrystallization frommethylene chloride gave fine colorless needles, mp 229°-231°.

EXAMPLE 298-Chloro-6-(2-fluorophenyl)-N,1-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-3-carboxamide

A mixture of 1.0 g (2.1 mmole) of8-chloro-6-(2-fluorophenyl)-1-methyl-3-[(trichloromethyl)carbonyl]-2H,4H-pyrrolo[3,4-d][2]benzazepineand 70 ml of methanol saturated with methylamine was heated in a bomb ona steam bath for 48 hr. The mixture was cooled, and the methanol wasremoved at reduced pressure to give a solid residue. The residue waspartitioned between methylene chloride and water. The methylene chloridelayer was separated, dried with anhydrous sodium sulfate, andconcentrated at reduced pressure to give (mp 252°-255° C.) tan needles.Recrystallization from methylene chloride gave colorless needles, mp266°-268° C.

EXAMPLE 308-Chloro-6-(2-fluorophenyl)-1-(2-propenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepineand8-chloro-6-(2-fluorophenyl)-3-(2-propenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine

By means of a syringe 20 ml (12.5 mmole) of a 0.62 M tetrahydrofuransolution of lithium diisopropylamide was added dropwise to a solution of3.1 g (9.6 mmole) of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine in 75 mlof dry tetrahydrofuran which was cooled to -20° C. The solution wasstirred at -20° C. for 5 minutes followed by the addition of 5.0 ml (55mmole) of allyl bromide. The mixture was allowed to warm to roomtemperature and stirred for 2 hours. Water was added and the mixtureextracted with ether. The ether solution was washed with water, driedover anhydrous sodium sulfate, and concentrated at reduced pressure togive an amber oil. Purification by column chromatography (silica gel, 70g; eluent 5% ether in methylene chloride) gave the less polar compound.Recrystallization from a mixture of ether and petroleum ether gave creamprisms, mp 135°-140° C. (foams).

The methanesulfonate salt of8-chloro-6-(2-fluorophenyl)-3-(2-propenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepinewas prepared by adding equimolar amounts of the base and methanesulfonicacid to methanol and isolated by precipitating the salt with theaddition of ether. Recrystallization from a mixture of methanol andether gave orange prisms, mp 243°-244° C.

The final compound to be eluted gave starting material (mp 226°-227° C.)which was identical to an authentic sample.

EXAMPLE 318-Chloro-6-(fluorophenyl)-2-(2-propenyl)-4H-pyrrolo[3,4-d][2]benzazepine

In one portion, 0.7 g (2.2 mmole) of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was addedto a solution of 0.3 g (2.6 mmole) of potassium t-butoxide in 30 ml ofdry dimethyl formamide which was cooled to 0° C. After stirring for 15minutes, 1.0 ml (11 mmole) of allyl bromide was added and the mixturewas allowed to warm to room temperature. Water was added and the mixturewas extracted with methylene chloride. The methylene chloride solutionwas washed with water, dried over anhydrous sodium sulfate, andconcentrated at reduced pressure to give a yellow oil. Purification bycolumn chromatography (silica gel, 20 g; eluent 5% ether in methylenechloride) gave a yellow oil. Crystallization from a mixture of ether andpetroleum ether gave a tan solid (mp 100°-102° C.). Recrystallizationfrom a mixture of ether and petroleum ether gave colorless prisms, mp104°-106° C.

EXAMPLE 328-Chloro-6-(2-fluorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine

In one portion, 0.7 g (2.2 mmole) of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was addedto a solution of 0.3 g (2.6 mmole) of potassium t-butoxide in 30 ml ofdry dimethylformamide which was cooled to 0° C. After stirring for 15minutes 1.0 ml (16 mmole) of methyl iodide was added, and the mixturewas allowed to warm to room temperature. Water was added, and themixture was extracted with methylene chloride. The methylene chloridesolution was washed with water, dried over anhydrous sodium sulfate, andconcentrated at reduced pressure to give a yellow oil. Purification bycolumn chromatography (silica gel, 20 g; eluent 5% ether in methylenechloride) gave a tan solid (mp 142°-144° C.). Recrystallization from amixture of ether and petroleum ether gave cream colored prisms, mp144°-146° C.

EXAMPLE 33 4-[4-Chloro-2-(2-fluorobenzoyl)phenyl]-5-(2-propenyl)-1H-pyrrole-3-carbonitrile

A mixture of 3.1 g (11 mmole) of3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile, 3.0 g (12mmole) of 1-tosyl-3-butenyl-isocyanide.sup.(1), and 25 ml of dimethylsulfoxide in 50 ml of ether was added dropwise to a suspension of 0.8 g(16.5 mmole) of 50% sodium hydride in mineral oil and 100 ml of ether.When the addition was complete stirring was continued for 2 hours. Themixture was diluted with water and the ether layer was separated. Theaqueous solution was extracted with ether. The combined ether extractswere washed with water, dried over anhydrous sodium sulfate andconcentrated at reduced pressure to give a dark oil. Purification bycolumn chromatography (silica gel, 150 g; eluent 5% ether in methylenechloride) gave colorless needles, (mp 142°-144° C.). Recrystallizationfrom a mixture of ether and petroleum ether gave colorless needles, mp142°-144° C.

EXAMPLE 348-Chloro-6-(2-fluorophenyl)-1-(2-propenyl)2H,-4H-pyrrolo[3,4-d][2]benzazepine

A mixture of 0.7 g (2 mmole) of4-[4-chloro-2-(2-fluorobenzoyl)phenyl-5-(2-propenyl)-1H-pyrrole-3-carbonitrileand 0.7 g (18 mmole) of lithium aluminum hydride in 50 ml oftetrahydrofuran was stirred at room temperature for 48 hours. The excesslithium aluminum hydride was discharged by the dropwise addition of asaturated aqueous solution of potassium sodium tartarate. The mixturewas diluted with methylene chloride and the methylene chloride solutionwas separated, dried over anhydrous sodium sulfate and concentrated atreduced pressure to give 4-aminomethyl-4-{4-chloro-2-[(2-fluorophenyl)hydroxymethyl]phenyl}-2-(2-propenyl)-1H-pyrrole as a mixture due torestricted rotation and supported by thin layer chromatography and itsnmr spectrum.

A mixture of 150 mg (0.4 mmole) of4-aminomethyl-4-{4-chloro-2-[(2-fluorophenyl)hydroxymethyl]phenyl}-2-(2-propenyl)-1H-pyrrole and 0.6 g (7.3 mmole) ofmanganese dioxide in 30 ml of tetrahydrofuran was refluxed for 2hours.The mixture was cooled and filtered over celite. The filtrate wasconcentrated at reduced pressure to give a red oil. Purification bycolumn chromatography (silica gel, 10 g; eluent 5% ether in methylenechloride) gave the end product as a tan solid, (mp 212°-214° C.).Recrystallization from a mixture of ether and methylene chloride gavecolorless prisms, mp 213°-215° C. which were identical in every respectto an authentic sample.

EXAMPLE 358-Chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine

A mixture of 1.0 g (3 mmole) of4-[4-chloro-3-(2-fluorobenzoyl)phenyl]-5-methyl-1H-pyrrole-3-carbonitrileand 1.0 g (26 mmole) of lithium aluminum hydride in 100 ml oftetrahydrofuran was stirred at room temperature for 24 hours. The excesslithium aluminum hydride was discharged by the dropwise addition of asaturated aqueous solution of potassium sodium tartarate. The mixturewas diluted with methylene chloride and the methylene chloride solutionwas separated, dried over anhydrous sodium sulfate, and concentrated atreduced pressure to give 4-aminomethyl-3-{4-chloro-2-[(2-fluorophenyl)hydroxymethyl]phenyl}-2-methyl-1H-pyrrole a mixture due to restrictedrotation and supported by thin layer chromatography and its nmrspectrum.

A mixture of 150 mg (0.43 mmole) of4-aminomethyl-3-{4-chloro-2-[(2-fluorophenyl)hydroxymethyl]phenyl}-2-methyl-1H-pyrrole and 600 mg (7.3 mmole) ofmanganese dioxide in 30 ml of tetrahydrofuran was refluxed for 2 hours.The mixture was cooled and filtered over celite. The filtrate wasconcentrated at reduced pressure to give an amber oil. Purification bycolumn chromatography (silica gel, 10 g; eluent 5% ether in methylenechloride) gave a cream colored solid. Recrystallization from ether gavecolorless needles, mp 226°-227° which was identical in every respect toan authentic sample.

EXAMPLE 368-Chloro-6-(2-fluorophenyl)-1-methyl-3-(2-propynyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine

By means of a syringe 7 ml (4.2 mmole) of a 0.62 M tetrahydrofuransolution of lithium diisopropylamide was added dropwise to a solution of1.3 g (4.0 mmole) of8-chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepinein 30 ml of dry tetrahydrofuran which was cooled to -20° C. The solutionwas stirred at -20° C. for 5 minutes followed by the addition of 2.4 ml(25 mmole) of 80% propargyl bromide in toluene. The mixture was allowedto warm to room temperature and stirred for 2 hours. Water was added andthe mixture was extracted with ether. The ether solution was washed withwater, dried over anhydrous sodium sulfate, and concentrated at reducedpressure to give an amber foam. Purification by column chromatography(silica gel, 20 g; eluent 5% ether in methylene chloride) gave a foam.Crystallization from a mixture of ether and petroleum ether gave creamprisms. (mp 179-180).

EXAMPLE 37

    __________________________________________________________________________     TABLET FORMULATION (Wet granulation)                                         __________________________________________________________________________    Item                                                                             Ingredients    mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                 __________________________________________________________________________    1. 8-chloro-6-(2-chloro-                                                                        1     5     10    25                                           phenyl)-2H,4H--                                                               pyrrolo[3,4-D] [2]                                                            benzazepine or                                                                8-chloro-1-methyl-6-                                                          (2-fluorophenyl)-2H--pyrrolo                                                  [3,4-D] [2] benzazepine                                                    2. Lactose        202   232   261   280                                       3. Modified Starch                                                                              25    35    45    55                                        4. Pregelatinized Starch                                                                        20    25    30    35                                        5. Distilled Water q.s.                                                                         --    --    --    --                                        6. Magnesium Stearate                                                                           2     3     4     5                                            Weight of tablet                                                                             250                                                                              mg 300                                                                              mg 350                                                                              mg 400                                                                              mg                                     __________________________________________________________________________    Procedure:                                                                    1. Mix Items 1-4 in a suitable mixer.                                         2. Granulate with sufficient distilled water to proper consistency.            Mill.                                                                        3. Dry in a suitable oven.                                                    4. Mill and mix with magnesium stearate for 3 minutes.                        5. Compress on a suitable press equipped with appropriate                     __________________________________________________________________________    punches.                                                                  

EXAMPLE 38

    __________________________________________________________________________     TABLET FORMULATION (Direct compression)                                      __________________________________________________________________________    Item                                                                             Ingredients    mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                 __________________________________________________________________________    1. 8-chloro-6-(2-chloro-                                                                        1     5     10    25                                           phenyl)-2H,4H--                                                               pyrrolo[3,4-D] [2]                                                            benzazepine or                                                                8-chloro-1-methyl-6-                                                          (2-fluorophenyl)-2H--pyrrolo                                                  [3,4-D] [2] benzazepine                                                    2. Lactose        221   217   212   181                                       3. Avicel         45    45    45    55                                        4. Direct Compression Starch                                                                    30    30    30    35                                        5. Magnesium Stearate                                                                           3     3     3     4                                            Weight of tablet                                                                             300                                                                              mg 300                                                                              mg 300                                                                              mg 300                                                                              mg                                     __________________________________________________________________________    Procedure:                                                                    1. Mix Item 1 with an equal amount of lactose. Mix well.                      2. Mix with Items 3, and 4, and the remaining amount of Item 2. Mix           well.                                                                         3. Add magnesium stearate and mix for 3 minutes.                              4. Compress on a suitable press equipped with appropriate                     __________________________________________________________________________    punches.                                                                  

EXAMPLE 39

    __________________________________________________________________________     CAPSULE FORMULATION                                                          __________________________________________________________________________    Item                                                                             Ingredients    mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                 __________________________________________________________________________    1. 8-chloro-6-(2-chloro-                                                                        1     5     10    25.                                          phenyl)-2H,4H--                                                               pyrrolo[3,4-D] [2]                                                            benzazepine or                                                                8-chloro-1-methyl-6-                                                          (2-fluorophenyl)-2H--pyrrolo                                                  [3,4,-D] [2] benzazepine                                                   2. Lactose        203   293.5 328   372.5                                     3. Starch         30    35    40    30                                        4. Talc           15    15    20    20                                        5. Aerosol OT     1     1.5   2     2.5                                          Capsule fill weight                                                                          250                                                                              mg 350                                                                              mg 400                                                                              mg 450                                                                              mg                                     __________________________________________________________________________    Procedure:                                                                    1. Mill Items 1, 2, 3, and 5 in a suitable mixer. Mill.                       2. Add talc and mix well.                                                     3. Encapsulate on suitable equipment.                                         __________________________________________________________________________

EXAMPLE 404-[4-Chloro-2-(2-chlorobenzoyl)phenyl]-5-methyl-1H-pyrrole-3-carbonitrile(Product 1) and6-chloro-8-(2-chlorophenyl)-1,8-dihydro-8-hydroxy-2-methylindeno[2,1-b]pyrrole-3-carbonitrile(Product 2)

A mixture of 33.9 g (0.11 mmol) of3-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-propenenitrile, 20 g (0.96 mol)of 1-tosylethyl isocyanide in a mixture of 150 ml of dimethyl sulfoxideand 190 ml of ether was added dropwise to a suspension of 4.6 g (0.1mol) of a 50% mineral oil dispension of sodium hydride in 100 ml ofether which was immersed in a room temperature water bath. Stirring atroom temperature was continued for 2 hr. The mixture was diluted with1.2 l of water and 40 ml of 1 N hydrochloric acid and extracted withmethylene chloride. The methylene chloride solution was washed withwater, dried over anhydrous sodium sulfate and concentrated at reducedpressure to give a dark green oil. Crystallization from a mixture ofether and petroleum ether gave Product 1 (mp 206°-208°) as tan crystals.Recrystallization from ether gave Product 1 as colorless crystals, mp210° -211°.

A second crop of crystals which were Product 2 (mp 221°-225°) wasobtained from ether. Recrystallization from ether gave Product 2 as paleyellow prisms, mp 232°-237°.

EXAMPLE 418-Chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine

A mixture of 8.5 g (24 mmol) of4-[4-chloro-2-(2-chlorobenzoyl)phenyl]-5-methyl-1H-pyrrole-3-carbonitrile,1 spoonful of Raney nickel and 250 ml of glacial acetic acid washydrogenated on a Parr apparatus of 55 psi overnight. The catalyst wasremoved by filtration and the acetic acid was removed at reducedpressure. The residue was diluted with water, basififed withconcentrated ammonium hydroxide and the resulting precipitate wascollected by filtration. The precipitate was dissolved intetrahydrofuran, dried over anhydrous sodium sulfate and concentrated atreduced pressure. The residue was crystallized from a mixture of etherand petroleum ether to give off-white cyrstals (mp 219°-222°).Recrystallization from a mixture of ether and methylene chloride gavecolorless crystals, mp 221°-225°.

EXAMPLE 428-Chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine

The preparation of8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]-benzazepinewas conducted in the same manner as the preparation of8-chloro-6-(2-fluorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine(Example 32) to give colorless prisms, mp 167°-168°.

The methanesulfonate salt of8-chloro-6-(2-chlorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepinewas prepared by adding equimolar amounts of the base compound andmethanesulfonic acid to methanol and isolated by precipating the saltwith the addition of ether. Recrystallization from a mixture of methanoland ether gave the methanesulfonate salt as orange prisms, mp 200°-203°.

EXAMPLE 438-Chloro-2-[2-(diethylamino)ethyl]-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepinedihydrochloride

In one portion 2.0 g (6.5 mmol) of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was addedto 0.9 g (8 mmol) of potassium t-butoxide in 35 ml of dimethylformamidewhich was cooled to 0°. After stirring for 15 min, 3 ml (9 mmol) of a 3M toluene solution of diethylaminoethyl chloride was added. The mixturewas allowed to warm to room temperature and stir for 2 hr. The mixturewas diluted with water and extracted with methylene chloride. Themethylene chloride solution was washed with water, dried over anhydroussodium sulfate and concentrated at reduced pressure. Purification of theresidue by column chromatography (25 g, silica gel; eluent 4:1 methylenechloride:ether) gave an off-white solid, mp 110°-112°. The white solidwas dissolved in 10 ml of 1.4 M methanolic hydrogen chloride and thesolution was diluted with ether. The resulting precipitate was collectedby filtration to give the dihydrochloride salt as an orange solid.Recrystallization from a mixture of methylene chloride and ether gavethe dihydrochloride salt as orange crystals, mp 229°-231°.

EXAMPLE 448-Chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-aceticacid methyl ester

In one portion 2.0 g (6.4 mmol) of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was addedto a solution of 0.9 g (8 mmol) of potassium t-butoxide in 30 ml ofdimethylformamide which was cooled to 0°. After stirring for 15 min, 0.7ml (7.5 mmol) of methyl bromoacetate was added. The mixture was stirredfor 5 min, diluted with water and extracted with ether. The ethersolution was washed with water, dried over anhydrous sodium sulfate andconcentrated at reduced pressure to dryness. Purification of the residueby column chromatography gave a pale yellow oil.

EXAMPLE 458-Chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylicacid methyl ester

In one portion 6.0 g (18.3 mmol) of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was addedto a solution of 3.0 g (26.5 mmol) of potassium t-butoxide in 50 ml ofdimethylformamide which was cooled to 0°. When solution was complete 1.8ml (2.3 g; 24.5 mmol) of methyl chloroformate was added and theresulting mixture was stirred for 15 min. The mixture was diluted with150 ml of water and the resulting precipitate was collected byfiltration. The precipitate was dissolved in methylene chloride andwashed with water. The methylene chloride solution was dried overanhydrous sodium sulfate and concentrated at reduced pressure. Theresidue crystallized from ether to give an off-white solid.Recrystallization from a mixture of methylene chloride and ether gaveoff-white fine needles, mp 185°-186° (dec.).

EXAMPLE 468-Chloro-6-(2-fluorophenyl)-2-methyl-2H,6H-pyrrolo[3,4-d][2]benzazepine

In one portion 3.0 g (9.5 mmol) of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was addedto a mixture of 1.5 g (13.2 mmol) of potassium t-butoxide and 100 ml ofdimethyl sulfoxide which was cooled in a water bath to 15°. The mixturewas stirred for 10 min followed by the addition of 4.0 ml (64 mmol) ofmethyl iodide. After stirring for 30 min the mixture was diluted withwater and extracted with ether. The ether solution was washed withwater, dried over anhydrous sodium sulfate and concentrated at reducedpressure. The solid residue was recrystallized from a mixture of etherand methylene chloride to give colorless needles, mp 215°-217°.

The mother liquors, by thin layer chromatography contained a mixture ofthe end product and the isomeric compound8-Chloro-6-(2-fluorophenyl)-2-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine.No effort was made in the purification of the mixture.

EXAMPLE 478-Chloro-6-(2-fluorophenyl)-2,5-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepin-5-iumiodide

In one portion 2.0 g (6.4 mmol) of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was addedto a solution of 0.9 g (8.0 mmol) of potassium t-butoxide in 30 ml ofdimethylformamide which was cooled to 0°. After stirring for 5 min 2.0ml (32 mmol) of methyl iodide was added and stirring was continued for 1hr. Water was added and the mixture was extracted with ether. The ethersolution was washed with water, dried over anhydrous sodium sulfate andconcentrated at reduced pressure to give a waxy solid. Purification bycolumn chromatography (silica gel; eluent 5% ether in methylenechloride) gave colorless crystals, mp 142°-143°.

The aqueous dimethylformamide solution was extracted with methylenechloride. The methylene chloride solution was washed with water, driedover anhydrous sodium sulfate and concentrated at reduced pressure todryness. Trituration of the residue with a mixture of methanol and ethergave the end product as an orange solid. Recrystallization from amixture of methanol and ether gave orange prisms, mp 228°-231°.

EXAMPLE 488-Chloro-6-(2-chlorophenyl)-2,5-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepin-5-iumiodide

In one portion 3.0 g (9.2 mmol) of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was addedto a solution of 1.35 g (12 mmol) of potassium t-butoxide in 30 ml ofdimethylformamide which was cooled to 0°. After stirring for 15 min 5 ml(80 mmol) of methyl iodide was added. The mixture was warmed to roomtemperature and stirred for 4 hr. The mixture was diluted with water andextracted with methylene chloride. The methylene chloride solution waswashed with water, dried over anhydrous and sodium sulfate andconcentrated at reduced pressure to a red oil. Crystallization wasinduced by the addition of a small amount of methanol to give a yellowsolid. Recrystallization from a mixture of methanol and ether gave fineorange needles, mp 195°-197°.

EXAMPLE 498-Chloro-6-(2-chlorophenyl)-2,5-dimethyl-5,6-dihydro-2H,4H-pyrrolo[3,4-d][2]benzazepine

Portionwise 0.2 g (52 mmol) of sodium borohydride was added to asolution of 3.0 g (6.3 mmol) of8-chloro-6-(2-chlorophenyl)-2,5-dimethyl-2H,4H-pyrrolo[3,4-d][2]benzazepin-5-iumiodide in 50 ml of methanol which was cooled to 0°. The mixture wasstirred at 0° for 20 min followed by the removal of the methanol atreduced pressure. The residue was partitioned between methylene chlorideand water. The methylene chloride solution was washed with water andsaturated aqueous sodium chloride, dried over anhydrous sodium sulfate,and concentrated at reduced pressure to give a pale yellow oil.Crystallization from ether gave colorless crystals, mp 154°-155°.

EXAMPLE 508-Chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-ethanol

A solution of 2.3 g (6.0 mmol) of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-aceticacid methyl ester in 25 ml of tetrahydrofuran was added dropwise to asolution of 0.5 g (13 mmol) of lithium aluminum hydride in 30 ml oftetrahydrofuran which was cooled to -78°. The reaction was allowed towarm to 0° and was stirred for 2 hr. The excess lithium aluminum hydridewas discharged by the addition of 0.6 ml of water, 0.6 ml of 10% sodiumhydroxide and 2.0 ml of water. The resulting precipitate was removed byfiltration and the filtrate was concentrated at reduced pressure todryness. The residue crystallized from ether to give a white solid.Recrystallization from a mixture of ether and petroleum ether gavecolorless prisms, mp 145°-147°.

EXAMPLE 518-Chloro-6-(2-chlorophenyl)-5,6-dihydro-2H,4H-pyrrolo[3,4-d][2]benzazepine

In five portions 0.5 g (7.9 mmol) of sodium cyanoborohydride and 35 mlof a 1 M methanol solution of methanesulfonic acid was added over 4 hrto a solution of 2.0 g (6.1 mmol) of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine in 50 mlof methanol which was cooled to 0°. When the addition was completestirring was continued overnight at room temperature. The solution wasbasified with 40% aqueous sodium hydroxide and diluted with water. Theresulting precipitate was collected by filtration to give a white solid.Recrystallization from a mixture of ether and methylene chloride gavecolorless crystals, mp 211°-212°.

EXAMPLE 521-[8-Chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepin-3-yl]-2,2,2-trichloroethanone

A mixture of 0.7 g (2.2 mmol) of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine and 2.0ml (18 mmol) of trichloroacetyl chloride in 20 ml of methylene chloridewas refluxed for 7 days. The resulting precipitate was collected byfiltration and partitioned between methylene chloride and saturatedaqueous sodium bicarbonate. The methylene chloride solution was driedover anhydrous sodium sulfate and concentrated at reduced pressure togive a white solid mp 240°-245° (dec).

EXAMPLE 538-Chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-3-carboxaldehyde

A solution of 3.0 ml (33 mmol) of phosphorous oxychloride in 20 ml ofmethylene chloride was added dropwise to a solution of 3.0 g (9.1 mmol)of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine in 40ml of dimethylformamide which was cooled to 0°. Stirring at 0° wascontinued for 2 hr. The mixture was poured into a saturated solution ofaqueous sodium carbonate and extracted with methylene chloride. Themethylene chloride solution was washed with water, dried over anhydroussodium sulfate and concentrated at reduced pressure to dryness.Purification by column chromatography (silica gel, 100 g; eluent, 50%(v/v) ethyl acetate in methylene chloride) gave a light pink solid, mp270°-274°. Recrystallization from a mixture of ethyl acetate andmethylene chloride gave peach colored prisms, mp 276°-277°.

EXAMPLE 548-Chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-3-carboxylic acid hemietherate

A solution of 1.5 g (9.5 mmol) of potassium permanganate in 150 ml of50% aqueous acetone was added dropwise to a solution of 1.6 g (4.5 mmol)of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-3-carboxaldehydein 100 ml of acetone. After 2.5 hr the mixture was diluted with asaturated aqueous solution of sodium bisulfite, neutralized with theaddition of acetic acid and extracted with methylene chloride. Themethylene chloride solution was dried over anhydrous sodium sulfate andconcentrated at reduced pressure to dryness. Trituration of the residuewith methylene chloride gave yellow crystals, mp 216°-218°.Recrystallization from a mixture of ethanol and ether gave yellowprisms, mp 252°-254° (dec).

EXAMPLE 558-Chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4]-d[2]benzazepine-3-carboxylicacid methyl ester methanesulfonate

A solution of 0.8 g (2.2 mmol) of crude8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-3-carboxylicacid in 20 ml of a 50% mixture of tetrahydrofuran and methylene chloridewas added 20 ml of a 1 M etherial solution of diazomethane. The excessdiazomethane was discharged with the addition of acetic acid. Theorganic solution was washed with saturated aqueous sodium bicarbonate,dried over anhydrous sodium sulfate and concentrated at reduced pressureto dryness. The residue was purified by column chromatography (silicagel, 20 g; eluent, 20% ether in methylene chloride) to give a paleyellow oil. The oil was dissolved in methanol containing 1 ml of a 1 Mmethanol solution of methanesulfonic acid and the salt was isolated bythe addition of ether. Recrystallization from a mixture of methanol andether gave the methanesulfonate salt as yellow crystals, mp 273°-274°(dec.).

EXAMPLE 56 8-Chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-3-carboxaldehyde

By means of a syringe 0.6 ml (6.5 mmol) of phosphorous oxychloride wasadded to a solution of 0.7 g (2.0 mmol) of8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepinein 8 ml of dimethylformamide which was cooled to 0°. The mixture wasstirred at 0° for 1 hr, poured into 50 ml of saturated aqueous sodiumcarbonate and extracted with methylene chloride. The methylene chloridesolution was washed with water, dried over anhydrous sodium sulfate andconcentrated at reduced pressure to give a red amorphous solid.Purification by column chromatography (silica gel, 20 g; 4% ether inmethylene chloride, eluent) gave an off-white solid. Recrystallizationfrom a mixture of methylene chloride and ethyl acetate gave off-whitecrystals, mp 274°-276°.

EXAMPLE 578-Chloro-6-(2-chlorophenyl)-3-(hydroxymethyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine

In one portion 0.2 g (5.2 mmol) of sodium borohydride was added to 0.9 gof8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-3-carboxaldehydein 20 ml of methanol which was cooled to 0°. After stirring at 0° for 30min, water was added and the resulting precipitate was collected byfiltration to give a tan amorphous solid (mp 170°-180° dec.). Allattempts to purify this product led to the introduction of impurities bydecomposition.

EXAMPLE 588-Chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-5-oxide

Method A. A solution of 4.0 g (20 mmol) of 85% m-chloroperbenzoic acidin 50 ml of methylene chloride was added dropwise to a solution of 5.0 g(15 mmol) of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine in 250 mlof methylene chloride which was cooled to 0°. The mixture was stirred at0° for 2 hr and washed with saturated aqueous sodium bicarbonate, waterand saturated aqueous sodium sulfate and concentrated at reducedpressure to give an oil. Crystallization from ethyl acetate gave a creamcolored solid. Recrystallization from a mixture of methylene chlorideand ether gave fine colorless needles, mp 233°-235°.

Method B. A mixture of 1.0 g (2.4 mmol) of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylicacid methyl ester 5-oxide and 2.5 ml of 3 N aqueous sodium hydroxide ina mixture of 10 ml of methanol and 50 ml of tetrahydrofuran was stirredat room temperature for 20 min. The mixture was concentrated at reducedpressure and the residue was partitioned between water and methylenechloride. The methylene chloride solution was washed with water, driedover anhydrous sodium sulfate, and concentrated at reduced pressure. Theresidue was triturated with a mixture of tetrahydrofuran and ether togive an off-white solid, mp 239°-240°. Recrystallization from a mixtureof ether and methylene chloride gave fine colorless needles, mp241°-242°. Spectroscopic analysis clearly show the products as identicalalthough the melting points differ.

EXAMPLE 598-Chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylicacid methyl ester 5-oxide

A mixture of 4.2 g (11 mmol) of 8-chloro-B6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylic acidmethyl ester and 3.15 g (14.5 mmol) of m-chloroperbenzoic acid in 100 mlof methlene chloride was stirred at 0° for 2.5 hr. The mixture waswashed with saturated aqueous sodium bicarbonate and saturated aqueoussodium chloride, dried over anhydrous sodium sulfate and concentrated atreduced pressure to dryness. The residue was crystallized from ether togive a white solid, mp 224°-226°. Recrystallization from a mixture ofether and methylene chloride gave colorless prisms, mp 226°-227°.

EXAMPLE 604-(Acetyloxy)-8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylicacid methyl ester

A mixture of 7.6 g (19 mmol) of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylicacid methyl ester 5-oxide and 200 ml of acetic anhydride was stirred at70° for 12 hr and at 105° for 5 hr. The acetic anhydride solution wasconcentrated at reduced pressure. The residue was dissolved in methylenechloride and washed with saturated aqueous sodium bicarbonate andsaturated aqueous sodium chloride. The methylene chloride solution wasdried over anhydrous sodium sulfate and concentrated at reduced pressureto give an oil. Purification by column chromatography (50 g, neutralalumina; 5% ether in methylene chloride, eluent) gave a tan solid, mp175°-177°. Recrystallization from ether gave an off-white solid, mp177°-178°.

EXAMPLE 618-Chloro-6-(2-chlorophenyl)-4-methoxy-2H,4H-pyrrolo[3,4-d][2]benzazepine

A mixture of 1.0 g (2.2 mmol) of4-(acetyloxy)-8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylicacid methyl ester and 2.5 ml of 3 N aqueous sodium hydroxide solution ina mixture of 25 ml of tetrahydrofuran and 10 ml of methanol was stirredat 0° for 30 min. The mixture was diluted with water and extracted withmethylene chloride. The methylene chloride solution was washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfateand concentrated at reduced pressure to dryness. The residue wastriturated with a mixture of ether and methylene chloride to give acream colored solid, mp 215°-218°. Recrystallization from a mixture oftetrahydrofuran and hexane gave tan prisms, mp 221°-224°.

EXAMPLE 628-Chloro-2-methyl-4-methoxy-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine

In one portion 1.0 g (2.8 mmol) of8-chloro-6-(2-chlorophenyl)-4-methoxy-2H,4H-pyrrolo[3,4-d][2]benzazepinewas added to a solution of 0.35 g (3.0 mmol) of potassium t-butoxide in20 ml of dimethylformamide which was cooled to 0°. After stirring for 15min, 0.3 ml (4.8 mmol) of methyl iodide was added. The mixture wasstirred for 5 min, diluted with water and extracted with ether. Theether solution was washed with water, dried over anhydrous sodiumsulfate, and concentrated at reduced pressure to give a pale yellow oil.Purification by column chromatography (silica gel, 25 g; 5% ether inmethylene chloride, eluent) gave an off-white solid, mp 128°-130°.Recrystallization from a mixture of ether and petroleum ether gaveoff-white prisms, mp 128°-130°.

EXAMPLE 63 3-[2-(2-Fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile

A solution of 5.0 g (14 mmol) of 5-chloro-2'-fluoro-2-iodobenzophenone,2 ml (14.3 mmol) of triethylamine, 2 ml (30 mmol) of acrylonitrile and35 mg (1.5 mmol) of palladium acetate was refluxed under an atmosphereof argon for 16 hr. The mixture was diluted with 100 ml of 1 Nhydrochloric acid and the resulting precipitate was collected byfiltration. The precipitate was washed with ether and air dried to givean off-white solid, mp 130°-133°.

EXAMPLE 648-Chloro-2-[2-(dimethylamino)ethyl]-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepinedihydrochloride

The preparation of8-chloro-2-[2-(dimethylamino)ethyl]-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepinedihydrochloride was conducted in the same manner as the preparation of8-chloro-2-[3-(dimethylamino)propyl]-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepinedihydrochloride to give the product as yellow crystals, mp 264°-266°.

EXAMPLE 658-Chloro-2-[3-(dimethylamino)propyl]-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepinedihydrochloride

In one portion 1.5 g (4.8 mmol) of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was addedto a solution of 0.6 g (5.3 mmol) of potassium t-butoxide in 25 ml ofdimethylformamide which was cooled to 0°. After stirring for 15 min, 5.2ml (10.4 mmol) of a 2 M toluene solution of dimethylaminopropyl chloridewas added. The mixture was warmed to room temperature and stirred for 4hr. The mixture was diluted with water and extracted with methylenechloride. The methylene chloride solution was washed with water, driedover anhydrous sodium sulfate and concentrated at reduced pressure.Purification of the residue by column chromatography (silica gel, 25 g;eluents, 4:1 ration of methylene chloride:ether followed by 1:2:7 ratioof methanol:ether:methylene chloride) gave a colorless oil. The oil wasdissolved in an excess of methanolic hydrogen chloride and the solutionwas concentrated at reduced pressure. Crystallization of the residuefrom a mixture of isopropanol and ether gave an orange solid, mp258°-260°.

EXAMPLE 668-Chloro-2-[2-(diethylamino)ethyl]-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine

In one portion 2.1 g (6.4 mmol) of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was addedto a solution of 0.8 g (7.0 mmol) of potassium t-butoxide in 35 ml ofdimethyl formamide which was cooled to 0°. After stirring for 15 min 2.5ml (7.5 mmol) of a 3 M toluene solution of diethylaminoethyl chloridewas added. The mixture was warmed to room temperature and stirred for 3hr. The mixture was diluted with water and extracted with methylenechloride. The methylene chloride solution was washed with water, driedover anhydrous sodium sulfate and concentrated at reduced pressure.Purification of the residue by column chromatography (25 g, silica gel;eluent 4:1 methylene chloride:ether) gave an off-white solid, mp130°-131°.

EXAMPLE 678-Chloro-2-[2-(diethylamino)ethyl]-5,6-dihydro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepinedihydrochloride

Portionwise over a 30 min. period, 0.3 g (5.3 mmol) of sodiumcyanoborohydride was added to a solution of 0.3 g (0.75 mmol) of8-chloro-2-[2-(diethylamino)ethyl]-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepinedihydrochloride. During the course of the reaction a total of 6.0 mL(8.4 mmol) of a 1.4 M methanol solution of hydrogen chloride was addedto maintain an acidic pH. The methanol was removed at reduced pressureand the residue partitioned between aqueous ammonium hydroxide andether. The ether solution was dried over anhydrous sodium sulfate andconcentrated at reduced pressure to dryness. The residue was dissolvedin an excess of methanolic hydrogen chloride and 50 mL of isopropanol.Concentration of the solution at reduced pressure gave the product as awhite solid. Recrystallization from a mixture of ether and methanol gavethe product as colorless needles, mp 265°-270° C. (dec.).

What is claimed:
 1. A compound of the formula ##STR24## wherein R₁ " isselected from the group consisting of hydrogen, lower alkyl, C₃ to C₇alkenyl and C₃ to C₇ alkynyl; R₅ is hydrogen or halogen and R₆ ishalogen.